Nebivolol is a novel β-adrenergic receptor (β-AR) blocker with anti-inflammatory and antioxidant properties. The NLRP3 inflammasome plays a pivotal role in the pathogenesis of obesity-induced vascular dysfunction. Our study aimed to explore the effect of nebivolol on the NLRP3 inflammasome and vascular remodeling in diet-induced obese rats. Eight-week-old Sprague-Dawley male rats were fed with either a standard chow diet or a high-fat diet (HFD) for 8 weeks. Next, the obese rats were subdivided into 3 groups as follows: (1) HFD control group, (2) HFD with low doses of nebivolol (5 mg/kg·d), and (3) HFD with high doses of nebivolol (10 mg/kg·d). A 4-week treatment with nebivolol improved acetylcholine-induced vascular relaxation in accordance with an increased aortic endothelial nitric oxide synthase. Nebivolol attenuated NLRP3 inflammasome activation and suppressed autophagy. In parallel, nebivolol enhanced the levels of phase-II detoxifying enzymes, including superoxide dismutase and catalase. These effects were associated with an increased β3-AR level. Moreover, nebivolol treatment significantly increased Adenosine 5'-monophosphate (AMP)-activated protein kinase activity and decreased phosphorylation of the mammalian target of rapamycin. These results demonstrated that nebivolol improves obesity-induced vascular remodeling by attenuating NLRP3 inflammasome activation and restoring the antioxidant defense.